Behavioral characterization of co-exposure to cannabinoids and hormonal contraceptives in female rats

Hormonal contraceptives are among the most widely used drugs by young healthy women to block ovulation and avoid pregnancy. They reduce the ovarian secretion of estradiol and progesterone, hormones that also modulate neuronal plasticity, cognitive functions, emotions and mood. Cannabis is the most commonly used illicit drug worldwide and its use is increasing among young women, many of which regularly take the "pill". Despite evidence of a bidirectional interaction between the endocannabinoid system and gonadal hormones, only very few studies have examined the consequences of cannabis consumption in young females under hormonal contraceptives treatment. To fill this gap, this study evaluated the behavioral effects of co-exposure to chronic 1) hormonal contraceptives, i.e., ethinyl estradiol (EE) plus levonorgestrel (LNG), one of the synthetic estrogen-progestin combinations of hormonal contraceptives, and 2) cannabinoid receptor agonist, i.e., WIN 55,212-2 (WIN), on motor activity, emotional state and cognitive functions in young adult female rats (8-11/experimental group). Hormonal and cannabinoid treatment started at post-natal day (PND) 52 and 56, respectively, while behavioral testing occurred between PND 84-95. The results show that chronic EE-LNG treatment, at doses (0.020 and 0.060 mg/rat, respectively) known to drastically reduce plasma progesterone levels, and the contextual exposure to WIN, at a dose (12.5 μg/kg/infusion) known to be rewarding in the rat, alters the hormonal milieu but does not cause further changes in locomotor activity compared to EE-LNG or WIN alone, and does not modify anxiety-like state (as measured by the elevated plus maze and the marble burying tests) and cognitive abilities (as measured by the novel object recognition and the prepulse inhibition tests) in young adult female rats. Although exposure to EE-LNG and WIN tends to increase the duration of immobility and to reduce the time spent swimming in the forced swimming test, there was not a significant additive effect suggestive of a depressive-like state. These findings allow deepening the current knowledge on the interaction between cannabinoid agonists and hormonal contraceptives and suggest that low, rewarding doses of cannabinoids do not significantly alter the motor and cognitive skills and do not induce anxiety or depressive-like states in females that use hormonal contraceptives.